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The apical Na+/K+/2Cl− cotransporter (NKCC2) mediates NaCl reabsorption by the thick ascending limb, contributing to maintenance of blood pressure (BP). Despite effective NKCC2 inhibition by loop diuretics, these agents are not viable for long-term management of BP due to side effects. Novel molecular mechanisms that control NKCC2 activity reveal an increasingly complex picture with interacting layers of NKCC2 regulation. Here, we review the latest developments that shine new light on NKCC2-mediated control of BP and potential new long-term therapies to treat hypertension.Emerging molecular NKCC2 regulators, often binding partners, reveal a complex overlay of interacting mechanisms aimed at fine tuning NKCC2 activity. Different factors achieve this by shifting the balance between trafficking steps like exocytosis, endocytosis, recycling and protein turnover, or by balancing phosphorylation vs. dephosphorylation. Further molecular details are also emerging on previously known pathways of NKCC2 regulation, and recent in-vivo data continues to place NKCC2 regulation at the center of BP control.Several layers of emerging molecular mechanisms that control NKCC2 activity may operate simultaneously, but they can also be controlled independently. This provides an opportunity to identify new pharmacological targets to fine-tune NKCC2 activity for BP management.